Deflazacort

JAYTHARI is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 2 years of age and older. JAYTHARI is a corticosteroid indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 2 years of age and older ( 1 )

Oral Suspension 22.75 mg/mL: White to off white homogeneous suspension Oral Suspension: 22.75 mg/mL ( 3)

JAYTHARI is contraindicated in patients with known hypersensitivity to deflazacort or to any of the inactive ingredients. Instances of hypersensitivity, including anaphylaxis, have occurred in patients receiving corticosteroid therapy [see Warnings and Precautions (5.15) and Adverse Reactions (6.2) ] . Hypersensitivity to deflazacort or any of the inactive ingredients in JAYTHARI ( 4 )

Alterations in Endocrine Function : Hypothalamic-pituitary-adrenal axis suppression, Cushing's syndrome, and hyperglycemia can occur; Monitor patients for these conditions with chronic use of JAYTHARI ( 2.3 , 5.1 ) Immunosuppression and Increased Risk of Infection: Increased risk of new, exacerbation, dissemination, or reactivation of latent infections, which can be severe and at times fatal; Signs and symptoms of infection may be masked ( 5.2 ) Alterations in Cardiovascular/Renal Function : Monitor for elevated blood pressure and sodium, and for decreased potassium levels ( 5.3 ) Gastrointestinal Perforation: Increased risk in patients with certain GI disorders; Signs and symptoms may be masked ( 5.4 ) Behavioral and Mood Disturbances: May include euphoria, insomnia, mood swings, personality changes, severe depression, and psychosis ( 5.5 ) Effects on Bones: Monitor for decreases in bone mineral density with chronic use of JAYTHARI ( 5.6 ) Ophthalmic Effects: May include cataracts, infections, and glaucoma; Monitor intraocular pressure if JAYTHARI is continued for more than 6 weeks ( 5.7 ) Vaccination: Do not administer live or live attenuated vaccines to patients receiving immunosuppressive doses of corticosteroids. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting JAYTHARI ( 5.8 ) Serious Skin Rashes: Discontinue at the first sign of rash, unless the rash is clearly not drug related ( 5.9 )

5.1 Alterations in Endocrine Function Corticosteroids, such as JAYTHARI, can cause serious and life-threatening alterations in endocrine function, especially with chronic use. Monitor patients receiving JAYTHARI for Cushing's syndrome, hyperglycemia, and adrenal insufficiency after JAYTHARI withdrawal. In addition, patients with hypopituitarism, primary adrenal insufficiency or congenital adrenal hyperplasia, altered thyroid function, or pheochromocytoma may be at increased risk for adverse endocrine events. Risk of Adrenal Insufficiency Following Corticosteroid Withdrawal Corticosteroids produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, with the potential for the development of secondary adrenal insufficiency after withdrawal of corticosteroid treatment. Acute adrenal insufficiency can occur if corticosteroids are withdrawn abruptly, and can be fatal. The degree and duration of adrenocortical insufficiency produced is variable among patients and depends on the dose, frequency, and duration of corticosteroid therapy. The risk is reduced by gradually tapering the corticosteroid dose when withdrawing treatment. This insufficiency may persist, however, for months after discontinuation of prolonged therapy; therefore, in any situation of stress occurring during that period of discontinuation, corticosteroid therapy should be reinstituted. For patients already taking corticosteroids during times of stress, the dosage may need to be increased. A steroid "withdrawal syndrome", seemingly unrelated to adrenocortical insufficiency, may also occur following abrupt discontinuance of corticosteroids. This syndrome includes symptoms such as anorexia, nausea, vomiting, lethargy, headache, fever, joint pain, desquamation, myalgia, and/or weight loss. These effects are thought to be due to the sudden change in corticosteroid concentration rather than to low corticosteroid levels. Cushing's Syndrome Cushing's syndrome (hypercortisolism) occurs with prolonged exposure to exogenous corticosteroids, including JAYTHARI. Symptoms include hypertension, truncal obesity and thinning of the limbs, purple striae, facial rounding, facial plethora, muscle weakness, easy and frequent bruising with thin fragile skin, posterior neck fat deposition, osteopenia, acne, amenorrhea, hirsutism and psychiatric abnormalities. Hyperglycemia Corticosteroids can increase blood glucose, worsen pre-existing diabetes, predispose those on long-term therapy to diabetes mellitus, and may reduce the effect of anti-diabetic drugs. Monitor blood glucose at regular intervals. For patients with hyperglycemia, anti-diabetic treatment should be initiated or adjusted accordingly. Considerations for Use in Patients with Altered Thyroid Function Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate a dose adjustment of the corticosteroid. When concomitant administration of corticosteroids and levothyroxine is required, administration of corticosteroid should precede the initiation of levothyroxine therapy to reduce the risk of adrenal crisis. Pheochromocytoma Crisis There have been reports of pheochromocytoma crisis, which can be fatal, after administration of systemic corticosteroids. In patients with suspected or identified pheochromocytoma, consider the risk of pheochromocytoma crisis prior to administering corticosteroids.

5.2 Immunosuppression and Increased Risk of Infection Corticosteroids, including JAYTHARI, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can: Reduce resistance to new infections Exacerbate existing infections Increase the risk of disseminated infections Increase the risk of reactivation or exacerbation of latent infections Mask some signs of infections Corticosteroid-associated infections can be mild but can be severe, and at times fatal. The rate of infectious complications increases with increasing corticosteroid dosages. Monitor for the development of infection and consider JAYTHARI withdrawal or dosage reduction as needed. Tuberculosis If JAYTHARI is used to treat a condition in patients with latent tuberculosis or tuberculin reactivity, reactivation of tuberculosis may occur. Closely monitor such patients for reactivation. During prolonged JAYTHARI therapy, patients with latent tuberculosis or tuberculin reactivity should receive chemoprophylaxis. Varicella Zoster and Measles Viral Infections Varicella and measles can have a serious or even fatal course in non-immune patients taking corticosteroids, including JAYTHARI. In corticosteroid-treated patients who have not had these diseases or are non-immune, particular care should be taken to avoid exposure to varicella and measles. If a JAYTHARI-treated patient is exposed to varicella, prophylaxis with varicella zoster immunoglobulin may be indicated. If varicella develops, treatment with antiviral agents may be considered. If a JAYTHARI-treated patient is exposed to measles, prophylaxis with immunoglobulin may be indicated. Hepatitis B Virus Reactivation Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids, including JAYTHARI. Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection. Screen patients for hepatitis B infection before initiating immunosuppressive (e.g., prolonged) treatment with JAYTHARI. For patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy. Fungal Infections Corticosteroids, including JAYTHARI, may exacerbate systemic fungal infections; therefore, avoid JAYTHARI use in the presence of such infections unless deflazacort is needed to control drug reactions. For patients on chronic JAYTHARI therapy who develop systemic fungal infections, JAYTHARI withdrawal or dose reduction is recommended. Amebiasis Corticosteroids, including JAYTHARI, may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating JAYTHARI in patients who have spent time in the tropics or patients with unexplained diarrhea. […]

The following serious adverse reactions are discussed in more detail in other sections: Alterations in Endocrine Function [see Warnings and Precautions (5.1) ] Immunosuppression and Increased Risk of Infection [see Warnings and Precautions (5.2) ] Alterations in Cardiovascular/Renal Function [see Warnings and Precautions (5.3) ] Gastrointestinal Perforation [see Warnings and Precautions (5.4) ] Behavioral and Mood Disturbances [see Warnings and Precautions (5.5) ] Effects on Bones [see Warnings and Precautions (5.6) ] Ophthalmic Effects [see Warnings and Precautions (5.7 )] Immunizations [see Warnings and Precautions (5.8) ] Serious Skin Rashes [see Warnings and Precautions (5.9) ] Effects on Growth and Development [see Warnings and Precautions (5.10) ] Myopathy [see Warnings and Precautions (5.11) ] Kaposi's Sarcoma [see Warnings and Precautions (5.12) ] Risk of Serious Adverse Reactions in Infants because of Benzyl Alcohol Preservative [see Warnings and Precautions (5.13) ] Thromboembolic Events [see Warnings and Precautions (5.14) ] Anaphylaxis [see Warnings and Precautions (5.15) ] The most common adverse reactions (≥10% for deflazacort and greater than placebo) are Cushingoid appearance, weight increased, increased appetite, upper respiratory tract infection, cough, pollakiuria, hirsutism, central obesity, and nasopharyngitis ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In Study 1 [see Clinical Studies (14) ] , the adverse reactions that were associated with deflazacort treatment discontinuation, in decreasing order of frequency, were weight increased, obesity, cataract, and sleep disorder. Most Common Adverse Reactions in Clinical Studies Table 1 lists the adverse reactions that occurred in ≥5% of patients in the 0.9 mg/kg/day deflazacort-treated group and that occurred more frequently than in placebo patients in Study 1, which included patients with DMD between the ages of 5 and 15 years. Table 1: Adverse Reactions that Occurred in ≥ 5% of Deflazacort-Treated Patients and Occurred More Frequently than in Placebo Patients with DMD (Study 1) Adverse Reaction Deflazacort 0.9 mg/kg/d (N=51) % at 12 weeks Placebo (N=50) % at 12 weeks 1 Cushingoid appearance 33 12 Weight increased 20 6 Increased appetite 14 2 Upper respiratory tract infection 12 10 Cough 12 6 Pollakiuria 12 2 Nasopharyngitis 10 6 Hirsutism 10 2 Central obesity 10 4 Erythema 8 6 Irritability 8 4 Rhinorrhea 8 0 Abdominal discomfort 6 2 1 At 12 weeks placebo patients were re-randomized to receive either deflazacort or an active comparator. Common adverse reactions (≥5% of deflazacort-treated patients) that occurred over 52 weeks of exposure to deflazacort 0.9 mg/kg/day in Study 1 and at a higher rate than deflazacort 0.9 mg/kg/day in the 12-week placebo-controlled phase of the trial include Cushingoid appearance (60%), hirsutism (35%), weight increased (28%), erythema (28%), central obesity (25%), abdominal pain/abdominal pain upper (18% combined), pollakiuria (15%), constipation (10%), irritability (10%), abnormal behavior (9%), pyrexia (9%), back pain (7%), rash (7%), contusion (6%), nausea (6%), psychomotor hyperactivity (6%), epistaxis (6%), and skin striae (6%). Study 1 also evaluated a higher dosage of deflazacort (1.2 mg/kg/day). Compared with the 0.9 mg/kg/day dosage, deflazacort 1.2 mg/kg/day over 52 weeks was associated with a higher incidence of certain adverse reactions, including Cushingoid appearance (69%), erythema (49%), hirsutism (37%), headache (34%), weight increased (32%), constipation (15%), abdominal pain upper (14%), skin striae (11%), acne (11%), and abdominal discomfort (8%). As there was no additional benefit with the 1.2 mg/kg/day dose of deflazacort, use of deflazacort 1.2 mg/kg/day is not recommended for the treatment of DMD [see Dosage and Administration (2.2) ] . In an additional clinical study of two years duration with extended follow-up (Study 2), many of the same adverse reactions were observed. In addition, musculoskeletal events associated with long-term steroid use were also observed, including muscle weakness, tendon disorder, and osteopenia. Less Common Adverse Reactions Observed in Clinical Studies Other adverse reactions (≥1% frequency in any deflazacort treatment group and greater than placebo) that were observed during the 12-week placebo-controlled phase of Study 1 are shown below. Eye Disorders: Lacrimation increased Gastrointestinal Disorders: Dyspepsia, nausea, gastrointestinal disorder General Disorders and Administration Site Conditions: Thirst Infections: Hordeolum, impetigo, influenza, otitis externa, pharyngitis, tooth abscess, urinary tract infection, viral infection Injury, Poisoning and Procedural Complications: Back injury, contusion, face injury, fibula fracture, greenstick fracture, heat exhaustion Investigations: Glucose urine present, heart rate irregular Musculoskeletal and Connective Tissue Disorders: Back pain, muscle spasms, myalgia, neck mass, neck pain, pain in extremity Nervous System Disorders: Dizziness, psychomotor hyperactivity Psychiatric Disorders: Affect lability, aggression, depression, emotional disorder, middle insomnia, mood altered, mood swings, sleep disorder Renal and Urinary Disorders: Chromaturia, dysuria, hypertonic bladder Reproductive System and Breast Disorders: Testicular pain Respiratory, Thoracic, and Mediastinal Disorders: Hypoventilation, rhinorrhea Skin and Subcutaneous Tissue Disorders: Acne, alopecia, dermatitis acneiform Vascular Disorders: Hot flush

6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of deflazacort worldwide or during post-approval use of other corticosteroids. These reactions are reported voluntarily from a population of uncertain size; therefore, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Leukocytosis Cardiac Disorder: Heart failure Eye Disorders: Chorioretinopathy, corneal or scleral thinning Gastrointestinal Disorders: Acute pancreatitis (especially in children), hemorrhage, peptic ulceration, perforation of peptic ulcer General Disorders and Administration Site Conditions: Edema, impaired healing Immune System Disorders: Hypersensitivity including anaphylaxis Metabolism and Nutrition Disorders: Impaired carbohydrate tolerance with increased requirement for anti-diabetic therapy, negative protein and calcium balance, potassium loss and hypokalemic alkalosis when co-administered with beta 2-agonist and xanthines Musculoskeletal and Connective Tissue Disorders: Avascular necrosis, muscle wasting, negative nitrogen balance, tendonitis and tendon rupture when co-administered with quinolones, vertebral and long bone fractures Nervous System Disorders: Aggravation of epilepsy, increased intra-cranial pressure with papilledema in children (pseudotumor cerebri) usually after treatment withdrawal, vertigo Psychiatric Disorders: Anxiety, cognitive dysfunction including confusion and amnesia, delusions, hallucinations, mania, suicidal thoughts Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis Vascular Disorders: Thromboembolism, in particular in patients with underlying conditions associated with increased thrombotic tendency, benign intracranial hypertension

Moderate or strong CYP3A4 inhibitors: Give one third of the recommended dosage of JAYTHARI ( 7.1 ) Avoid use of moderate or strong CYP3A4 inducers with JAYTHARI, as they may reduce efficacy ( 7.1) 7.1 CYP3A4 Inhibitors and Inducers Moderate or Strong CYP3A4 Inhibitors The active metabolite of deflazacort, 21-desDFZ, is a substrate of CYP3A4 [see Clinical Pharmacology (12.3) ] . Co-administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold. Therefore, give one third the recommended dosage of JAYTHARI when moderate or strong CYP3A4 inhibitors (e.g., clarithromycin, fluconazole, diltiazem, verapamil, grapefruit juice) are used concomitantly with deflazacort [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] . Moderate or Strong CYP3A4 Inducers Co-administration of deflazacort with rifampin, a strong CYP3A4 inducer, significantly decreased the exposure of 21-desDFZ. Avoid concomitant use of strong (e.g., efavirenz) or moderate (e.g., carbamazepine, phenytoin) CYP3A4 inducers with deflazacort [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] .

7.2 Neuromuscular Blockers Patients receiving corticosteroids, including JAYTHARI, and concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium) may be at increased risk of developing an acute myopathy [see Warnings and Precautions (5.11) ] .

8.1 Pregnancy Risk Summary Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. There are no adequate and well-controlled studies with deflazacort in pregnant women to inform drug-associated risks. Corticosteroids, including deflazacort, readily cross the placenta. Adverse developmental outcomes, including orofacial clefts (cleft lip, with or without cleft palate) and intrauterine growth restriction, and decreased birth weight, have been reported with maternal use of corticosteroids, including deflazacort, during pregnancy. Some epidemiologic studies report an increased risk of orofacial clefts from about 1 per 1,000 infants to 3 to 5 per 1,000 infants; however, a risk for orofacial clefts has not been observed in all studies. Intrauterine growth restriction and decreased birth weight appear to be dose-related; however, the underlying maternal condition may also contribute to these risks (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Animal reproduction studies have not been conducted with deflazacort. Animal reproduction studies conducted with other corticosteroids in pregnant mice, rats, hamsters, and rabbits using clinically relevant doses have shown an increased incidence of cleft palate. An increase in embryofetal death, intrauterine growth retardation, and constriction of the ductus arteriosus were observed in some animal species. Data Human Data Multiple cohort and case-controlled studies in humans suggest that maternal corticosteroid use during the first trimester increases the rate of cleft lip, with or without cleft palate, from about 1/1,000 infants to 3 to 5/1,000 infants. Two prospective case-controlled studies showed decreased birth weight in infants exposed to maternal corticosteroids in utero.

8.2 Lactation Risk Summary Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for deflazacort and any potential adverse effects on the breastfed infant from deflazacort. There are no data on the effects on milk production.

8.4 Pediatric Use The safety and effectiveness of deflazacort for the treatment of DMD have been established in patients 2 years of age and older. Use of deflazacort in pediatric patients is supported by a multicenter, randomized, double-blind, placebo- and active-controlled study in 196 males 5 to 15 years of age [see Clinical Studies (14) ] . Use of deflazacort in patients 2 years to less than 5 years of age is supported by the findings of efficacy and safety in patients 5 years and older with DMD. Safety and effectiveness in pediatric patients below the age of 2 years have not been established. JAYTHARI oral suspension contains benzyl alcohol and is not approved for use in pediatric patients less than 2 years of age. Serious adverse reactions including fatal reactions and "gasping syndrome" occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 mg/kg/day to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 mmol/L to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. When prescribing JAYTHARI oral suspension consider the combined daily metabolic load of benzyl alcohol from all sources including JAYTHARI oral suspension (JAYTHARI oral suspension contains 10.45 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. At the recommended dose of 0.9 mg/kg/day of JAYTHARI oral suspension, patients would receive approximately 0.4 mg/kg/day of benzyl alcohol [see Warnings and Precautions (5.13) ]. Juvenile Animal Toxicity Data Oral administration of deflazacort (0, 0.1, 0.3, and 1 mg/kg/day) to juvenile rats from postnatal day (PND) 21 to 80 resulted in decreased body weight gain and adverse effects on skeletal development (including decreased cellularity of growth plate and altered bone distribution) and on lymphoid tissue (decreased cellularity). A no-effect dose was not identified. In addition, neurological and neurobehavioral abnormalities were observed at the mid and/or high dose. Plasma 21-desDFZ exposure (AUC) at the lowest dose tested (0.1 mg/kg/day) was lower than that in humans at the recommended human dose of deflazacort (0.9 mg/kg/day).

8.5 Geriatric Use DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with deflazacort.

8.6 Renal Impairment No dose adjustment is required in patients with mild, moderate or severe renal impairment [see Clinical Pharmacology (12.3) ] .

8.7 Hepatic Impairment No dose adjustment is required in patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3 )] . There is no clinical experience in patients with severe hepatic impairment, and a dosing recommendation cannot be provided for patients with severe hepatic impairment.

Deflazacort is a corticosteroid prodrug, whose active metabolite, 21-desDFZ, acts through the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects. The precise mechanism by which deflazacort exerts its therapeutic effects in patients with DMD is unknown.